Immunotherapy toxicities- Diarrhea and colitis

 GI toxicity

Timing: 1 month after starting CTLA4 , 2-4 months after PDL1 and PD1. Can happen within 2 months of discontinuation

Symptoms: diarrhea, abd pain, fever, bleeding per rectum less common

Testing:

1. Rule out infectino: C dif, Gi multiplex stool, lactoferrin, calprotectin

2. Sensitivity of lactoferrin ( 90% on bx , 70% on endoscopy)

3. calprotectin-- higher levels predict higher risk of ulcers and serious findings on endoscopy

4. Do both lactoferrin and calprotectin if available. If lactoferrin is elevated at baseline, ( quick turnaround, if positive get endoscopy). Repeat calprotectin 2 months into rx. Lactoferrin not sensitive on treatment.

What are the high risk features associated with prolonged hospitalization and steroid refractoriness?

> 1 cm wide, Deep ulcers > 2mm, or > 3 in number--> start infliximab along with steroids

At baseline do a colonoscopy if lactoferrin elevated. If inflammation restricted to left colon ( better prognosis) alone, then ok to consider flex sig in the future i. e at 2 months

MD Anderson protocol

ESMO IO guidelines

What if there is no immune mediated colitis on endoscopy? Pt presents with diarrhea without colitis symptoms ( abd pain, rectal bleeding, blood or mucus in stool)

- GI  consult/ ID consult ( if positive CMV etc or immune compromised)

-bland food

- hydration 2-3 liters per day

- cholestyramine or colesevalem or mesalamine

What is the risk of recurrent colitis on rechallenge?

Recurrent rate of colitis is 35%

Immunotherapy toxicities- Cardiac

 Cardiac

Manifestations: myocarditis, pericarditis, vasculitis, ACS, CHF, conduction abnormalities, atrial and ventricular arrhythmias

sx: chest pain, dyspnea, palpitation, syncope

Mortality 20-50% ( compared to 2-5% with colitis)

Presentation: inflammatory manifestations -->within 3 months or first 4 cycles of rx; non inflammatory after  6 months

Pt on ICI presents with Afib--> check TSH, troponin, rule out myocarditis, rule out ACS.

Troponin I is specific but may take time to result.

Troponin T is non specific but is readily available.

Myocarditis: get Echo,  EKG continuous, Cardiac MRI with inflammatory images.

Troponin is elevated in 94% of cases, and NT-BNP is elevated in 2/3 cases. On echo EF can be preserved in 51% of patients with myocarditis and 38% of those with MACE. 

Endomyocardial bx is the gold standard for diagnosis.

PET /CT can also show cardiac inflammation.

MRI and bx concordance: 35 % if ICI myocarditis, 94% if viral myocarditis

Use of combination check point ie ipi nivo increases risk of myocarditis

Front line: IV methyl prednisolone 1 mg/kg bwt--> 3 days, improving --> Prednisone 1 mg/kg bwt, slow taper.

Not improving--> tocilizumab, MMF, supportive care as needed ECMO, pacemaker, endomyocardial bx, cardiac cath

uncomplicated IR-pericarditis with oral prednisolone and colchicine :500 μg twice daily

ICI myocarditis is a reason to permanently discontinue the drug.

Other aggressive therapies- IVIG, plasmapheresis, abatacept

Question: What immune related toxicity should you hold the check point inhibitor for grade 1 toxicity?

Ans- suspected cardiac toxicity. However if grade 1 a or 1 b ie inflammatory infiltrate without necrosis, no need for immune suppression. Good long term prognosis.

C4d pericapillary staining may be the reason plasma pheresis is effective.

EHA 2022 

ESMO IO toxicities

Additional rx considerations:

1. Abatacept CTLA 4 agonist

2. Alemtuzumab- CD 52Ab, used in cardiac allograft rejection

3. IVIG

4. Infliximab in steroid refractory- use with caution if CHF, 5 mg/kg rather than 10 mg/kg bwt

Additional reference

What is the overlap or 3 M syndrome?

Myocarditis had 44% overlap with myositis and myasthenia gravis

-high dose steroids in myasthenia can lead to need for intubation and worsening resp function

-troponin T remains higher for longer if they also have myositis. Use steroid sparing immunomodulatory therapy earlier on.

Myocarditis does not relapse typically but myositis can relapse.

Annals of Oncology supplement

 CV risk factors (cholesterol profile, blood pressure, HbA1c) and optimal CV risk factor management is recommended in all cancer survivors who have received ICI treatment and have a prognosis of >2 years. 

Blood journal snippets

 Odds ratio for VTE

• Heterozygous Prothrombin- less than 2
• FVL heterozygous- a little greater than 2
• Prothrombin homozygous- 3
• FVL homozygous- 6
• Double prothrombin + FVL heterozygous= 2+3= 5 ( additive risk not synergistic risk if heterozygous with double) Odds ratio of VTE 5 times.

ALL ph+

• Imatinib or Nilotinib can be used with induction. Don't omit cytarabine because relapse is higher if you do, although mortality was unchanged.OS 79% 4 yr survival.
• ALL relapse look for T 315 mutation, ponatinib may be needed
• Is allo HCT necessary if cytarabine is part of the consolidation regimen?  There did not seem to be a necessity.
• A blinatumomab based approach may be needed in over 60 yr when combined with TKI. However, CNS relapses are a problem with Blinatumomab + TKI. So CNS prophy needs to be optimized.

Ref: blood June 2024

Co-occurrence of arterial and venous thromboembolism

 Ref- Blood June 2024

1. AUGUSTUS trial- use apixaban with plavix in Afib patients undergoing PCI or had ACS. OK to drop aspirin.

2. Define the indication for antithrombotic and or antiplatelet therapy and how the rx can change depending on the phase of rx.

3. If a pt is on aspirin for primary prophylaxis and develops a VTE--> stop aspirin, ct DOAC per existing guidelines i.e 3-6 months full dose, followed by maintenance if unprovoked. For such a pt recommend statins, weight loss and DM/HTN management.

4.  Use PPI for GI prophy if DAPT of ir anticoagulant+ antiplatelet

5. Pt with hx of prior non embolic stroke on ASA develops PE--> stop ASA, switch to DOAC and ct

6. Recent MI, PCI, DES on DAPT, now with PE--> stop ASA, ct plavix, start DOAC if PCI was more than 30 days ago. DAPT plus DOAC only if very high risk of instent thrombosis typically first 30 days of DES. Typically stop all antiplatelets at 1 yr except high risk when it can be continued. ct DOAC at maintenance dose after 6 m.

7. Pt with peripheral arterial disease ( PAD) are at risk for limb loss and MI. If pt with PAD and hx of VTE on an anticoagulant now requires revascularization: 

- ct anticoag alone if after surgical revasc

- anticoag plus aspirin 1-3 months after endovascular revasc

DPI- 2.5 mg BID eliquis plus ASA 81 mg

Stable CAD and symptomatic PAD after revas--> use DPI regimen

8. If PAD pt on DPI gets a VTE, up the DOAC to rx dose for 3 months if provoked, keep the ASA to overlap with Eliquis full dose for the first month after the VTE. The remaining 2 months keep only Eliquis 5 mg BID, then drop to 2.5 mg BID, restart aspirin. Use PPI.

Follicular lymphoma review

 1. There is no cytogenetic abnormality that is diagnostic of FL

2. 60% express surface Ig M, 40% Ig G

3. Pediatric type in adults can have a grade 3 FL appearance, but is lacking in BCL2 IHC or t( 14;18) and has high cure rates. Typically stage I/II. Has mutations in MAP2K1 and loss of cmyc, BCL2, BCL6.

4. When FL involves the gut, it is usually in the duodenum and involves the mucosa alone. Duodenal-type FL should be differentiated from systemic FL involving the gastrointestinal tract. Features that point to systemic FL include transmural infiltration of the organ wall, regional lymph node involvement, and involvement of the large intestine.

5. Classical FL is the most common indolent NHL. There are 4 variants.

    a. In situ follicular neoplasia: no typical FL features in the LN but high expression of Bcl2 and CD10. Such patients require full work up to rule out FL. If they do not have FL, the prognosis is unclear.

    b. Duodenal variant as above

    c.  Pediatric-type FL should be distinguished from the more aggressive entity "large B-cell lymphoma with IRF4 rearrangement

6. Prognosis: FLIPI or PRIMA-PI

• High-risk FLIPI (three or more adverse factors) – median PFS 42 months, two-year OS 87 percent
• Intermediate-risk FLIPI (two adverse factors) – median PFS 70 months, two-year OS 94 percent
• Low-risk FLIPI (zero to one adverse factors) – median PFS 84 months, two-year OS 98 percent

7. Rx- III/IV FL 1/2/3a and II with bulk > 7 cm--> BR or BO based on Gallium study. Better PFS in 3 yr ( 7% better for Obin)